Purpose:To compare demarcation line depth (DD) and topographic changes among different corneal collagen cross-linking (CXL) protocols and to evaluate the relation of DD with medium-term efficacy of CXL in halting progression of keratoconus.Methods:The study included 124 patients (mean age 19 ± 4.8 years) with progressive keratoconus who underwent conventional (3 mW/cm2/30 min), accelerated (18 mW/cm2/5 min), or transepithelial (TE) CXL (3 mW/cm2/30 min) and followed up for at least 2 years. Baseline and final corneal topographic parameters and DD determined with anterior segment optical coherence tomography 1 month after CXL were compared among the protocols and the correlation between DD and topographic changes at the end of 24 months was analyzed. P < 0.05 was considered as statistically significant.Results:Mean DD was significantly higher in the conventional and accelerated groups (335.19 ± 71.13 m and 304.97 ± 94.45 m, respectively) compared with the TE group (239.92 ± 71.37 m) (P < 0.001). After conventional and TE CXL, keratometric parameters improved remarkably, whereas accelerated CXL only lowered K1 and Kmax (P < 0.05). No correlation was found between DD and topographic changes (P > 0.05). Progression was detected in 3 eyes in the conventional group (4.1%), 3 in the accelerated group (7.7%), and none in the TE group. The use of either riboflavin D or M made no differences in terms of DD and topographic parameters (P > 0.05).Conclusions:In conventional and accelerated protocols, corneal stromal demarcation line is deeper compared with TE CXL; however, the DD has no correlation with topographic changes, which means that DD is not a direct measure for the efficacy of CXL.